Background Raynaud's phenomenon (RP) occurs in >95% of patients (pts) with systemic sclerosis (SSc) and contributes to digital ischaemia that may lead to digital ulcers (DUs) and gangrene.1,2 Empirical treatment of SSc-associated RP includes oral vasodilators, particularly calcium channel blockers and intermittent intravenous prostacyclin analogues.3,4 However, there is a need to identify oral therapies that are more efficacious than those currently available.
Objectives To determine the activity of selexipag, an oral, selective, prostacyclin receptor agonist, on RP attack frequency in pts with SSc.
Methods The study comprised a placebo single-blind run-in phase of 2–4-weeks followed by an 8-week double-blind treatment phase. Pts (≥18 years) with definite SSc and ≥7 RP attacks on ≥5 days in the week before randomisation were assigned 1:1 to selexipag or placebo. Study drug was titrated to an individual highest tolerated dose (200–1600 μg BID). The primary efficacy endpoint was the number of RP attacks per week in the maintenance phase (5 weeks) as determined from the pt's daily entries in the eDiary, and was analysed using a negative binomial model adjusted for the baseline number of RP attacks. Other outcomes included Raynaud Condition Score (RCS),5 RP attack duration, new DU frequency, and treatment-emergent adverse events (AEs).
Results Baseline (BL) characteristics were comparable between the groups (selexipag n=36, placebo n=38). No significant difference in effect was demonstrated for selexipag vs placebo (observed average number of RP attacks per week during the maintenance phase: 18.0 [vs 22.4 at BL, selexipag, n=27], 14.2 [vs 21.5 at BL, placebo, n=32]), adjusted mean treatment difference 3.43 in favour of placebo. During the maintenance phase, 63.0% (selexipag) and 81.3% (placebo) of pts had an improvement in the average number of RP attacks per week vs BL. No significant treatment effect was observed on RCS, RP attack duration and new DU frequency. At least one AE occurred in 100% (selexipag) and 86.8% (placebo) of pts; ≥1 prostacyclin-associated AE occurred in 91.7% (selexipag) and 55.3% (placebo) of pts. AEs were mostly reported as mild (16.7% selexipag pts, 34.2% placebo pts) or moderate (61.1% selexipag pts, 44.7% placebo pts) in intensity.
Conclusions The primary efficacy endpoint was not met (no reduction in number of RP attacks per week for selexipag vs placebo). The robust study design may nevertheless provide a template for future studies in RP. The marked reduction in attack frequency on placebo may underlie failure to show additional potential benefit with selexipag, which should be considered when designing future studies in RP. The safety profile of selexipag was similar to previous studies,6 with no new safety signals identified.
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Acknowledgement The study was sponsored by Actelion Pharmaceuticals Ltd. Medical writing support was provided by Lynda McEvoy PhD, of ApotheCom Ltd, sponsored by Actelion.
Disclosure of Interest C. P. Denton Grant/research support from: Actelion Pharmaceuticals Ltd, CSL Behring, Novartis, Consultant for: Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Bayer, Inventiva, Takeda, Speakers bureau: Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Bayer, Inventiva, Takeda, Έ. Hachulla Grant/research support from: Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Consultant for: Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Bayer, Pfizer, Speakers bureau: Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Bayer, Pfizer, G. Riemekasten Consultant for: Bayer, Paid instructor for: Schering, Bayer, A. Schwarting Grant/research support from: Actelion Pharmaceuticals Ltd, Consultant for: GlaxoSmithKline, Speakers bureau: GlaxoSmithKline, J.-M. Frenoux Employee of: Actelion Pharmaceuticals Ltd, A. Frey Employee of: Actelion Pharmaceuticals Ltd, F.-O. Le Brun Employee of: Actelion Pharmaceuticals Ltd, A. Herrick Grant/research support from: Actelion Pharmaceuticals Ltd, Consultant for: Actelion Pharmaceuticals Ltd, Apricus, Speakers bureau: Actelion Pharmaceuticals Ltd
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